IMAGE: EVAN OTO/SCIENCE SOURCE370 28 JANUARY 2022 • VOL 375 ISSUE 6579 science.org SCIENCEM
ore than 50 years after the Summer
of Love, psychedelics are again the
rage. This time the love comes from
doctors beginning to embrace psy-
chedelics such as LSD and psilocy-
bin to treat depression, substance
abuse, and other serious mental health con-
ditions. But because the drugs cause halluci-
nations, their medical use requires intensive
monitoring by clinicians. That drives up
treatment costs, making psychedelics im-
practical for widespread therapeutic use.
In recent years, researchers have begun
to tweak psychedelics’ chemical structures,
aiming to make analogs that retain medi-
cal usefulness but don’t cause hallucina-
tions. Now, researchers report in Science
(p. 403) they’ve teased apart the molecular
interactions responsible for psychedelics’
antidepressive effects from those that cause
hallucinations. They used that knowledge
to make new compounds that appear to
activate brain cellular circuits that help re-
lieve depression without triggering a closely
related pathway involved in hallucinations.
So far, the compounds have only been stud-
ied in mice. But if such psychedelic analogs
work in humans, they could spawn new
families of pharmaceuticals.
“This work is going to generate a lot of
interest,” says Bryan Roth, a pharmacologist
at the University of North Carolina School
of Medicine, whose lab is also seeking non-
hallucinogenic psychedelic analogs.
The need is profound. Mental or neuro-
logical disorders are estimated to affect
roughly one-quarter of U.S. adults every year,
and therapies often don’t work. LSD, psilo-
cybin (the main ingredient in magic mush-
rooms), and other psychedelics might do
better. Studies have shown a single dose of
psilocybin can offer relief from depression for
months at a time, and last year, a clinical trial
of 3,4-methylenedioxymethamphetamine,
or ecstasy, showed it can alleviate post-traumatic stress disorder (Science, 21 May
2021, p. 774).
How these hallucinogens exert their ef-
fects remains something of a mystery. In the
brain, LSD, psilocybin, and other psychedelic
compounds bind to a class of receptors for
the neurotransmitter serotonin, known as
5-HT2AR. The receptors, a type of cell mem-
brane protein called a G-protein coupled
receptor (GPCR), trigger two effects: They
initiate a host of cellular responses, and they
recruit other proteins called beta-arrestins
that modulate GPCR activity.
Previous work in people showed halluci-
nogens strongly activate both the GPCR and
beta-arrestin pathways. In 2017, Sheng Wang,
then a postdoc in Roth’s lab, took first steps
toward showing why. He produced an x-ray
crystal structure—basically an atomic-scale
map—of LSD bound to a serotonin receptor
closely related to 5-HT2AR. It revealed that
LSD nestles into a pocket within the receptor
called the orthosteric binding pocket (OBP).
Now, Wang, at the Shanghai Institute
of Biochemistry and Cell Biology, and his
colleagues have produced six new crys-
tal structures of compounds including
LSD, psilocin (the active metabolite of
psilocybin), serotonin, and lisuride, a non-
hallucinogenic psychedelic analog, bound
to 5-HT2AR itself. Some of the compounds,
they found, touched not only OBP, but a
neighboring cavity known as the extended
binding pocket (EBP).
To make sense of the binding patterns,
the researchers turned to behavioral studies
with mice injected with the different drugs.
The team watched for freezing responses
and head twitches, mouse behaviors strongly
associated with depression and hallucina-
tion in humans, respectively. The results
suggested compounds including serotonin
that evoke more beta-arrestin activity and
less GPCR activity were associated with anti-
depressive activity without hallucinations.And those compounds interacted more with
the EBP than the OBP.
So, Wang and his colleagues designed
structural cousins of LSD they thought
would favor binding to the EBP. They then
repeated the behavioral tests on mice given
these compounds and found that two of
them, dubbed IHCH-7079 and IHCH-7806,
did not trigger head twitches but did reduce
the freezing behavior, much as effective anti-
depressants do.
IHCH-7079 and -7806 aren’t the first com-
pounds to show potential as therapeutic
nonhallucinogenic analogs of psychedelics.
Lisuride, which is used to treat Parkinson’s
disease and migraines, was first marketed in
the 1970s. But the compound interacts with
many receptors in the brain besides 5-HT2AR
and, as a result, has side effects including
nausea and low blood pressure.
In 2020, researchers led by David Olson, a
chemist at the University of California, Davis,
reported in Nature that a nonhallucinogenic
analog of the psychedelic compound ibogaine
called tabernanthalog showed antidepressive
effects in rodents. Last year in Cell, Olson’s
team reported related nonhallucinogenic
compounds that appear more potent than
tabernanthalog. Delix Therapeutics, a com-
pany Olson co-founded, is working to com-
mercialize his compounds and related
nonhallucinogenic experimental drugs as
treatments for depression and other con-
ditions. Brigitte Robertson, the company’s
chief medical officer, says she expects it to
begin its first clinical trials later this year.
If any of the new compounds work to
improve mental health as effectively and as
quickly as psychedelics seem to, “it would
change the world of psychiatric care,” she
says. But even if these first compounds don’t
pass muster, the new structural insights into
how these compounds work give medicinal
chemists a road map for taking the halluci-
nations out of the healing. jPsychedelics
without
hallucinations?
Chemical relatives of LSD appear
to treat depression in mice
PHARMACOLOGYBy Robert F. ServiceLSD’s chemical
structure provided
inspiration for
new compounds.